rs45517932

chr6-52024685-G-Achr6-52024685-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_138694.4(PKHD1):c.5125C>T(p.Leu1709Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00598 in 1,614,206 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 6.54

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_138694.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0142250955).
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.5125C>T	p.Leu1709Phe	missense_variant	32/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.5125C>T	p.Leu1709Phe	missense_variant	32/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.5125C>T	p.Leu1709Phe	missense_variant	32/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00282 AC: 709 AN: 251342 Hom.: 3 AF XY: 0.00297 AC XY: 404 AN XY: 135836

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00623 AC: 9103 AN: 1461870 Hom.: 42 Cov.: 34 AF XY: 0.00603 AC XY: 4387 AN XY: 727238

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74490

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00636

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00526 Hom.: 2

Bravo AF: 0.00362

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 06, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2020	This variant is associated with the following publications: (PMID: 24162162, 30809968, 19940839, 20413436, 16133180, 15805161, 15108277, 12874454, 12846734) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKHD1: BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2022	Variant summary: PKHD1 c.5125C>T (p.Leu1709Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251342 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0028 vs 0.0071), allowing no conclusion about variant significance. However, this variant was observed in high allele frequency (as high as 1.5%) in healthy controls in multiple publications and classified as polymorphism (Rossetti_2003, Bergmann_2014, Sharp_2005, Losekoot_2005). c.5125C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Gunay-Aygun_2010, Denamur_2010, Bullich_2018). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four have classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.71	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.53
MVP		0.95
MPC		0.39
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45517932; hg19: chr6-51889483; COSMIC: COSV99049427;